4-hydroxybenzomorphans

ABSTRACT

4-Hydroxybenzomorphans containing carboxamide or thiocarboxamide at the 3-position are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications. A compound of formula 
                         
is disclosed, as are pharmaceutically acceptable acid addition salts, such as acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid or p-toluenesulfonic acid salts. These compounds are useful for the treatment of pain.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 11/760,039, filed Jun. 8, 2007, now allowed, which was a divisionalapplication of U.S. application Ser. No. 11/266,651, filed Nov. 3, 2005,and issued as U.S. Pat. No. 7,262,298 on Aug. 28, 2007. U.S. applicationSer. No. 11/266,651 claims priority from U.S. Provisional Application60/625,348 filed Nov. 5, 2004. The entire disclosures of each of theprior applications are hereby incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to 4-hydroxybenzomorphans substituted at the3-position with carboxamide or thiocarboxamide. The compounds are usefulas analgesics, anti-diarrheal agents, anticonvulsants, antitussives,anti-cocaine, and anti-addiction medications.

BACKGROUND OF THE INVENTION

Opiates have been the subject of intense research since the isolation ofmorphine in 1805, and thousands of compounds having opiate oropiate-like activity have been identified. Many opioidreceptor-interactive compounds including those used for producinganalgesia (e.g., morphine) and those used for treating drug addiction(e.g., naltrexone and cyclazocine) have been employed in human therapy.Almost all therapeutically useful opioids in the benzazocine andmorphinane classes have a phenolic hydroxyl group (OH) at a positionwhich is numbered “8” in the numbering system used for2,6-methano-3-benzazocines [e.g., cyclazocine and EKC(ethylketocyclazocine)] and which is numbered “3” in the numberingsystem used for morphinanes (e.g., morphine).

Although the compounds of the present invention do not possess the furanring of the morphinans, the morphinan numbering system will be used:

2,6-Methano-3-benzazocines are also known as benzomorphans, and thisterminology will be used interchangeably herein.

Until the publications of Wentland et al., [BioOrg. Med. Chem. Lett. 11,623-626 (2001) and BioOrg. Med. Chem. Lett. 11, 1717-1721 (2001)] theuniform experience in the art of the past seventy years had been thatremoval or replacement of the phenolic 3-hydroxy group had led topharmacologically inactive compounds.

SUMMARY OF THE INVENTION

We have now found that when the 3-hydroxyl group is replaced by a numberof small, polar, neutral residues, such as carboxamide andthiocarboxamidegroups, the adjacent 4-position may be substituted with ahydroxyl to produce compounds with an extraordinary affinity for theopioid receptor. The compounds of the invention are therefore useful asanalgesics, anti-pruritics, anti-diarrheal agents, anticonvulsants,antitussives, anorexics, and anti-obesity drugs and as treatments forhyperalgesia, drug addiction, respiratory depression, dyskinesia, pain(including neuropathic pain), irritable bowel syndrome andgastrointestinal motility disorders.

In one aspect, the invention relates to compounds of formula I:

A compound of formula:

wherein

-   A is chosen from —C(═O)NH₂ and —C(═S)NH₂;-   R² and R^(2a) are both hydrogen or taken together R² and R^(2a) are    ═O;-   R³ is chosen from hydrogen, lower alkyl, alkenyl, aryl,    heterocyclyl, benzyl and hydroxyalkyl;-   R⁴ is chosen from hydrogen, hydroxy, amino, lower alkoxy, C₁-C₂₀    alkyl and C₁-C₂₀ alkyl substituted with hydroxy or carbonyl;-   R¹¹ is hydrogen;-   R¹² is chosen from hydrogen, hydroxy, lower alkoxy and —NR¹³R¹⁴; or    together, R¹¹ and R¹² form a carbonyl or a vinyl substituent;-   R¹³ and R¹⁴ are chosen independently from hydrogen and C₁ to C₇    hydrocarbon; and    the dotted line represents an optional double bond.

In another aspect, the invention relates to methods for treating adisease or condition by altering a response mediated by an opioidreceptor. The method comprises bringing a compound of formula I intocontact with an opioid receptor. Diseases and conditions that areamenable to therapy with the compounds of the invention include pain,pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motilitydisorder, obesity, respiratory depression, convulsions, coughing,hyperalgesia and drug addiction. Drug addiction, as used herein,includes alcohol, nicotine, opiate and cocaine addiction. There isevidence in the literature that the compounds may also be useful asimmunosuppressants and antiinflammatories and for reducing ischemicdamage (and cardioprotection), for improving learning and memory, andfor treating urinary incontinence.

DETAILED DESCRIPTION OF THE INVENTION

From many years of SAR studies, it is known that the hydroxyl ofmorphinans and benzomorphans interacts with a specific site in theopiate receptor. Previous exploration of the tolerance of this site forfunctional groups other than phenolic hydroxyls has almost uniformlyresulted in the complete or near-complete loss of opioid binding. Wehave earlier reported (WO 02/36573) that the hydroxyl could be replacedwith one of several bioisosteres. Although a fairly wide range ofprimary and secondary carboxamides, as well as carboxylates,aminomethyl, hydroxymethyl and even dihydroimidazolyl exhibited bindingin the desired range below 25 nanomolar, optimal activity was observedwith a carboxamido, thiocarboxamido, hydroxyamidino or formamido group.We have now found that benzomorphans having a hydroxyl at 4 and thebioisostere “A” at position 3 have a surprising level of opioidactivity.

The phenolic 3-hydroxyl functionality of benzomorphans and morphinanscan be chemically converted to an amide by a simple, flexible andconvenient route described in WO 02/36573 and in WO 2004/007449, andthiocarboxamido, hydroxyamidino and formamido compounds are also easilysynthesized as described in those publications. Preferred residues A are—C(═O)NH₂ and —C(═S)NH₂.

It is known in the art that compounds that are μ, δ and κ agonistsexhibit analgesic activity; compounds that are selective μ agonistsexhibit anti-diarrheal activity and are useful in treating dyskinesia; μantagonists and κ agonists are useful in treating heroin, cocaine,alcohol and nicotine addiction; κ agonists are also anti-pruritic agentsand are useful in treating hyperalgesia. In general, the dextrorotatoryisomers of morphinans are useful as antitussives and anticonvulsants.

Exemplary opioid receptor ligands having known high affinity are shownin the following Chart.

Replacement of

in the compounds of the Chart produces compounds that exhibit strongaffinity for opioid receptors.

Other opioid receptors are reported in Aldrich, J. V. “Analgesics” inBurger's Medicinal Chemistry and Drug Discovery, M. E. Wolff ed., JohnWiley & Sons 1996, pages 321-44, the disclosures of which areincorporated herein by reference.

The affinities of the compounds of the invention are determined by themethod described in Wentland et al. [BioOrg. Med. Chem. Lett. 9. 183-187(2000)]. Antinociceptive activity is evaluated by the method describedin Jiang et al. [J. Pharmacol. Exp. Ther. 264, 1021-1027 (1993), page1022] or by the method described in Neumeyer et al. [J. Med. Chem. 46,5162 (2003). We have examined the receptor binding of compounds offormula I in a series of analogs of known compounds in which the OH isreplaced by the A group and a hydroxyl is introduced adjacent the Agroup. The data is shown in Tables 1, 2, 3, and 4. Data for thestandards used are also shown in the tables. The results of these invitro tests are accepted by persons of skill in the art as predictive oftherapeutic utility in vivo.

TABLE I Naltrexone series K_(i) (nM ± S.E.)

Sam- A or A^(a) [³H]DAMGO [³H]Naltrindole [³H]U69,593 ple or A^(b) (μ)(δ) (κ) 1 A^(a) = —OH 0.17 ± 0.03  11 ± 1.1 0.31 ± 0.03 (naltrexone) 2A^(a) = —CONH₂  1.9 ± 0.21  110 ± 8.1    22 ± 0.85 3 A = —CONH₂ 0.052 ±0.004  2.6 ± 0.26  0.23 ± 0.018 4 A = —OCH₃  6.7 ± 0.46 >10 μM   12 ±0.29 26 A = —CSNH₂  1.2 ± 0.093 140 ± 11   5.0 ± 0.72 24 A^(b) = —CONH₂ 0.16 ± 0.011  4.2 ± 0.74  0.29 ± 0.015

TABLE II Morphine series K_(i) (nM ± S.E.)

Sam- [³H]DAMGO [³H]Naltrindole [³H]U69,593 ple A^(a) (μ) (δ) (κ) 5 A^(a)= —OH 0.88 ± 0.14 140 ± 18   24 ± 2.3 (morphine) 6 A^(a) = —CONH₂  34 ±1.8 1900 ± 81  2000 ± 97 

TABLE III Oxymorphone series K_(i) (nM ± S.E.)

Sam- [³H]DAMGO [³H]Naltrindole [³H]U69,593 ple A (μ) (δ) (κ) 7 A = —OCH₃  15 ± 0.33 2000 ± 80 740 ± 25  7,8-dehydro 8 A = —OCH₃  4.6 ± 0.65 1200± 65  350 ± 8.5  7,8-dihydro

TABLE IV Nalbuphine series K_(i) (nM ± S.E.)

Sam- A or A^(a) [³H]DAMGO [³H]Naltrindole [³H]U69,593 ple or A^(b) orA^(c) (μ) (δ) (κ) 10 A^(a) = —OH  1.6 ± 0.37 580 ± 80   3.0 ± 0.63(nalbuphine) 11 A^(a) = —CONH₂  3.8 ± 0.62 150 ± 82  0.46 ± 0.04 21 A =—CONH₂  0.13 ± 0.0083  4.2 ± 0.36  0.27 ± 0.013 22a A^(b) = —CONH₂  0.52± 0.014  78 ± 7.0 9.0 ± 1.9 22b A^(c) = —CONH₂ 0.072 ± 0.008  3.9 ± 0.420.34 ± 0.05Definitions

Throughout this specification the terms and substituents retain theirdefinitions.

Alkyl is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. Lower alkyl refers to alkyl groupsof from 1 to 6 carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, s-and t-butyl,cyclopropyl, cyclobutyl and the like. Preferred alkyl groups are thoseof C20 or below. Cycloalkyl is a subset of alkyl and includes cyclichydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkylgroups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.

Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to four carbons.

Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9-or 10-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-memberedaromatic or heteroaromatic ring system containing 0-3 heteroatomsselected from O, N, or S. The aromatic 6- to 14-membered carbocyclicrings include, e.g., benzene, naphthalene, indane, tetralin, andfluorene and the 5- to 10-membered aromatic heterocyclic rings include,e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole,furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

Arylalkyl means an alkyl residue attached to an aryl ring. Examples arebenzyl, phenethyl and the like. Heteroarylalkyl means an alkyl residueattached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl,pyrimidinylethyl and the like.

Heterocycle means a cycloalkyl or aryl residue in which one to two ofthe carbons is replaced by a heteroatom such as oxygen, nitrogen orsulfur. Heteroaryls form a subset of heterocycles. Examples ofheterocycles that fall within the scope of the invention includepyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline,tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonlyreferred to as methylenedioxyphenyl, when occurring as a substituent),tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine,thiophene, furan, oxazole, oxazoline, isoxazole, dioxane,tetrahydrofuran and the like.

Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer to alkyl,aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in eachresidue are replaced with halogen, hydroxy, loweralkoxy, carboxy,carboalkoxy, carboxamido, cyano, carbonyl, —NO2, —NR1R2; alkylthio,sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl,phenoxy, benzyloxy, heteroaryloxy, or substituted phenyl, benzyl,heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

Virtually all of the compounds described herein contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, as well as their racemic andoptically pure forms. In general it has been found that the levo isomerof morphinans and benzomorphans is the more potent antinociceptiveagent, while the dextro isomer may be useful as an antitussive orantispasmodic agent. Optically active (R)- and (S)- isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

As used herein, and as would be understood by the person of skill in themedical art, to which the invention pertains, the recitation of thecompound includes pharmaceutically acceptable salts, hydrates, solvates,clathrates, and polymorphs. The term “pharmaceutically acceptable salt”refers to salts prepared from pharmaceutically acceptable non-toxicacids or bases including inorganic acids and bases and organic acids andbases. Salts may be prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Suitable pharmaceuticallyacceptable acid addition salts for the compounds of the presentinvention include acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. Theterm “solvate” refers to a compound—in this case eszopiclone—in thesolid state, wherein molecules of a suitable solvent are incorporated inthe crystal lattice. A suitable solvent for therapeutic administrationis physiologically tolerable at the dosage administered. Examples ofsuitable solvents for therapeutic administration are ethanol and water.When water is the solvent, the solvate is referred to as a hydrate. Ingeneral, solvates are formed by dissolving the compound in theappropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions.

The term “preventing” as used herein refers to administering amedicament beforehand to forestall or obtund an attack. The person ofordinary skill in the medical art (to which the present method claimsare directed) recognizes that the term “prevent” is not an absoluteterm. In the medical art it is understood to refer to the prophylacticadministration of a drug to substantially diminish the likelihood orseriousness of a condition, and this is the sense intended inapplicants' claims. The term “treating” includes prophylaxis as well asthe amelioration of the acute symptoms. Note that “treating” refers toeither or both of the amelioration of symptoms and the resolution of theunderlying condition. In many of the conditions of the invention, theadministration of the opioid may act not directly on the disease state,but rather on some pernicious symptom, and the improvement of thatsymptom leads to a general and desirable amelioration of the diseasestate.

Although this invention is susceptible to embodiment in many differentforms, preferred embodiments of the invention are shown. It should beunderstood, however, that the present disclosure is to be considered asan exemplification of the principles of this invention and is notintended to limit the invention to the embodiments illustrated. It maybe found upon examination that certain members of the claimed genus arenot patentable to the inventors in this application. In this event,subsequent exclusions of species from the compass of applicants' claimsare to be considered artifacts of patent prosecution and not reflectiveof the inventors' concept or description of their invention; theinvention encompasses all of the members of the genus I that are notalready in the possession of the public.

Abbreviations

The following abbreviations and terms have the indicated meaningsthroughout:

-   -   Ac=acetyl    -   AcOH=acetic acid    -   BNB=4-bromomethyl-3-nitrobenzoic acid    -   Boc=t-butyloxy carbonyl    -   Bu=butyl    -   c-=cyclo    -   DAMGO=Tyr-ala-Gly-NMePhe-NHCH₂OH    -   DBU=diazabicyclo[5.4.0]undec-7-ene    -   DCM=dichloromethane=methylene chloride=CH₂Cl₂    -   DEAD=diethyl azodicarboxylate    -   DIC=diisopropylcarbodiimide    -   DIEA=N,N-diisopropylethyl amine    -   DMAP=4-N,N-dimethylaminopyridine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethyl sulfoxide    -   DPPF=1,1′-bis(diphenylphosphino)ferrocene    -   DVB=1,4-divinylbenzene    -   EEDQ=2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline    -   Et₃N=triethylamine    -   EtOAc=ethyl acetate    -   Fmoc=9-fluorenylmethoxycarbonyl    -   GC=gas chromatography    -   HATU=O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HOBt=hydroxybenzotriazole    -   Me=methyl    -   mesyl=methanesulfonyl    -   MTBE=methyl t-butyl ether    -   NMO=N-methylmorpholine oxide    -   PEG=polyethylene glycol    -   Ph=phenyl    -   PhOH=phenol    -   PhN(Tf)₂=N-phenyltrifluoromethanesulfonimide    -   NP=pentafluorophenol    -   PPTS=pyridinium p-toluenesulfonate    -   PyBroP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate    -   rt=room temperature    -   sat'd=saturated    -   s-=secondary    -   t-=tertiary    -   Tf=triflate, CF₃SO₂O—    -   TBDMS=t-butyldimethylsilyl    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TMOF=trimethyl orthoformate    -   TMS=trimethylsilyl    -   tosyl=p-toluenesulfonyl    -   Trt=triphenylmethyl

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group that isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T. W. Greene [John Wiley & Sons, NewYork, 1991], which is incorporated herein by reference.

The following examples illustrate the syntheses of various compounds ofthe present invention having formula I, many of which are found in theTables. The remaining compounds listed in the Tables were prepared in asimilar fashion. Furthermore, the invention is not limited to thecompounds prepared in the examples or found in the Tables, and similarprocedures may be used to prepare additional compounds having formula I.

Unless indicated otherwise, the reactants and reagents used in theexamples are readily available materials. Such materials can beconveniently prepared in accordance with conventional preparatoryprocedures or obtained from commercial sources. ¹H NMR multiplicity dataare denoted by s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), and br (broad).

Example 1 Synthesis of 3-Carboxyamido-4-hydroxy-naltrexone Derivative 3

(A) Synthesis of 3-Carboxyamido-naltrexone 2

The triflate 11 of naltrexone was prepared according to the method ofWentland et al. (Bioorg. Med. Chem. Lett. 9, 183-187 (2000)), and thecarboxamide 2 was prepared by the method described by Wentland et al.[(Bioorg. Med. Chem. Lett. 11, 623-626 (2001); and Bioorg. Med. Chem.Lett. 11, 1717-1721 (2001)] involving Pd-catalyzed carbonylation of thetriflate 11 in the presence of ammonia and the Pd(0) ligand, DPPF([1,1′-bis(diphenylphosphino)ferrocene]) and DMSO.

(B) Synthesis of 3-Carboxyamido-4-hydroxy-naltrexone Derivative 3

Zinc dust (26 mg, 0.40 mmol) was added in portions to a solution of 2(50 mg, 0.14 mmol) in HCl (37%, 0.2 mL) and AcOH (2 mL) at reflux. Afterheating at reflux for a further 15 min, the reaction was cooled by theaddition of ice/water (10 mL) and basified (pH=9) with NH₃/H₂O, and thesolution was extracted with EtOAc (3×10 mL). The organic extracts werewashed with brine, dried, and concentrated. The residue was purified bycolumn chromatography (SiO₂, CH₂Cl₂, CH₃OH:NH₃/H₂O=15:1:0.01) to givecompound 3 as a foam (25 mg, 50%). ¹H NMR (CDCl3) δ 13.28(s, 1H, 4-OH),7.15(d, 1H, J=8.1, H-2), 6.47(d, 1H, J=8.4, H-1), 6.10(br, 1H, N-H),4.35(br, 1H, N-H), 4.04(dd, 1H, J=1.8, 13.5, H-5), 3.11(d, 1H, J=6),2.99(d, 1H, J=5.7), 2.94(s, 1H), 2.86(d, 1H, J=6), 2.84-2.75(m, 2H),2.65-2.61(m, 2H), 2.17-2.05(m, 1H), 1.89-1.84(m, 2H), 0.85(m, 1H),0.56-0.50(m, 2H), 0.13-0.09(m, 2H). [α]_(D) ²⁵=−98.4° (c=0.6, CH₂Cl₂).MS m/z (ESI) 371(MH⁺).

Example 2 Synthesis of 3-Methoxy-4-hydroxy-naltrexone Derivative 4

(A) Synthesis of 3-Methoxy-naltrexone Derivative 12

Using the procedure of Nan et al., J. Heterocyclic Chem. 34, 1195-1203(1997), 95% sodium hydride (22 mg, 0.87 mmol) was added to a solution ofnaltrexone 1 (200 mg, 0.58 mmol) in dry DMF (1 mL) at room temperature.After stirring for 15 min, the solution was cooled to 5° C. in an icebath and methyl iodide (40 μl, 99 mg, 0.70 mmol) was added. Afterstirring for another 15 min the reaction solution was concentrated invacuo. The residue was purified by flash chromatography (SiO₂,CH₂Cl₂:NH₃/H₂O=100:1) to give derivative 12 as a foam (131 mg, 67%). ¹HNMR (CDCl₃) δ 6.69(d, 1H, J=8.0, H-2), 6.61(d, 1H, J=8.0, H-1), 4.67(s,1H, H-5), 3.89(s, 3H, 3-OCH₃), 3.18(m, 1H), 3.06(m, 2H), 2.99(s, 1H),2.87(s, 1H), 2.70(m, 1H), 2.59(m, 1H), 2.40(m, 2H), 2.41(m, 2H), 2.31(m,2H), 2.12(m, 2H), 1.89(m, 2H), 1.59(m, 1H), 0.87(m, 1H), 0.55(m, 2H),0.15(m, 2H). [α]_(D) ²⁵=−181.7° (c=0.12, CH₂Cl₂). MS m/z (ESI) 356(MH⁺).

(B) Synthesis of 3-methoxy-4-hydroxy-naltrexone Derivative 4

A modification of a known procedure Coop et al., J. Med. Chem. 42,1673-1679 (1999) was used in this preparation. Zinc dust (114 mg, 1.72mmol) was added in portions to a solution of derivative 12 (122 mg, 0.34mmol) in HCl (37%, 0.2 mL) and AcOH (2 mL) at reflux. After heating atreflux for a further 15 min, the reaction was cooled by the addition ofice/water (20 mL) and basified (pH=9) with NH₃/H₂O, and the solution wasextracted with EtOAc (3×10 mL). The organic extracts were washed bybrine, dried, and concentrated. The residue was purified by columnchromatography (SiO₂, CH₂Cl₂:CH₃OH:NH₃/H₂O=20:1:0.01) to give compound 4as a foam (85 mg, 70%). ¹H NMR (CDCl₃) δ 6.67(d, 1H, J=8.0, H-2),6.56(d, 1H, J=8.0, H-1), 6.12(s, 1H, 4-OH), 3.94(d, 1H, J=13.0), 3.82(s,3H, 3-OCH₃), 3.10(m, 1H), 2.97(m, 1H), 2.80(m, 2H), 2.61(m, 1H), 2.36(m,2H), 2.15(m, 1H), 2.05(m, 2H), 1.82(m, 1H), 0.54(m, 2H), 0.12(m, 2H).[α]_(D) ²⁵=−96.2° (c=0.5, CH₂Cl₂). MS m/z (ESI) 358(MH⁻).

Example 3 Synthesis of 3-Methoxy-4-hydroxy-6-oxo-morphine Derivative 7

Using the procedure of Coop et al. (J. Med. Chem. 42, 1673-1679 (1999);and Heterocycles 50, 39-42 (1999)), n-butyllithium (1.52 M in hexane,1.6 mL, 2.50 mmol) was added to a solution of codeine (150 mg, 0.501mmol) in THF at −78° C. After stirring at −78° C. for 1 h, the slightyellow solution was warmed to room temperature and then stirred for 20min. The reaction was quenched with water (10 mL). The mixture wasextracted with CHCl₃ three times. The combined organic phases werewashed with brine, dried over sodium sulfate, filtered, and concentratedto give a solid residue, which was purified by flash chromatography(CH₂Cl₂:MeOH:NH₄OH 15:1:0.1) to give dehydro compound 7 as a white foam(114 mg, 0.381 mmol, 76%): ¹H NMR (500 MHz, CDCl₃) δ 6.68 (dd, 1H,J=10.0, 2.0 Hz), 6.64 (d, 1H, J=8.0 Hz), 6.55 (d, 1H, J=8.5 Hz), 6.00(bs, 1H), 5.89 (dd, 1H, J=10.0, 3.0 Hz), 4.26 (d, 1H, J=15.5 Hz), 3.81(s, 3H), 3.22 (m, 1H), 3.02 (d, 1H, J=18.5 Hz), 2.89 (s, 1H), 2.65 (m,1H), 2.54 (m, 1H), 2.43 (s, 3H), 2.38 (d, 1H, J=15.0 Hz), 2.07 (m, 1H),1.90 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 199.38, 149.53, 144.91, 144.58,130.75, 130.18, 122.86, 118.10, 108.71, 55.93, 55.80, 48.88, 47.02,46.95, 42.52, 40.47, 36.19, 24.32; MS (ESI) m/z 300 (M+H)⁺; Anal. Calcd.for C₁₈H₂₁NO₃.0.5H₂O: C 70.11, H 7.19, N 4.54. Found: C 69.94, H 6.87, N4.38.

Example 4 Synthesis of 3-Methoxy-4-hydroxy-6-oxo-7,8-dihydro-morphineDerivative 8

n-Butyllithium (1.52 M in hexane, 1.6 mL, 2.50 mmol) was added to asolution of codeine (150 mg, 0.501 mmol) in THF at −78° C. Afterstirring at −78° C. for 1 h, the slight yellow solution was warmed toroom temperature and then stirred for 20 min. The reaction was quenchedwith water (10 mL). The mixture was extracted with CHCl₃ three times.The combined organic phases were washed with brine, dried over sodiumsulfate, filtered, and concentrated to give a solid residue, which wasdissolved in AcOH (10 mL) and stirred with 10% Pd/C (54 mg) underhydrogen atmosphere (30 psi) for 20 h. The reaction mixture was filteredand concentrated to give an off-white residue, which was purified byflash chromatography (CH₂Cl₂:MeOH:NH₄OH 14:1:0.1) to give compound 8 asa white solid (125 mg, 0.415 mmol, 83%): ¹H NMR (500 MHz, CDCl₃) δ 6.67(d, 1H, J=8.0 Hz), 6.60 (d, 1H, J=8.0 Hz), 6.09 (s, 1H), 4.23 (dd, 1H,J=13.5, 2.5 Hz), 3.83 (s, 3H), 2.98 (d, 1H, J=18.5 Hz), 2.66 (m, 1H),2.44 (m, 2H), 2.42 (s, 3H), 2.24 (m, 3H), 2.06 (m, 1H), 1.86 (m, 3H),1.69 (m, 2H); MS (ESI) m/z 302 (M+H)⁺; Anal. Calcd. forC₁₈H₂₃NO₃.0.5H₂O: C 69.65, H 7.79, N 4.51. Found: C 70.04, H 7.68, N4.39.

Example 5 Synthesis of 3-Carboxyamido-4-hydroxy-hydrocodone Derivative17

(A) Synthesis of Morphine-3-carbonitrile Derivative 13

Morphine-3-triflate was prepared according to the procedure described byWentland et al. (J. Med. Chem. 3, 3558-3565 (2000)) and was then added(420 mg, 1.007 mmol) to a dry flask along with zinc cyanide (354 mg,3.022 mmol), and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.101mmol) under nitrogen atmosphere. The flask was then equipped with acondenser, sealed with a septum, and vacuumed/back-filled with argon for5 cycles. Dry DMF (2.0 mL) was added via syringe and the resultingmixture was stirred for 20 h at 120° C. The reaction was then cooled to25° C., diluted with EtOAc (30 mL), washed once with saturatedbicarbonate solution, twice with water, and once with brine. The organicphase was dried over sodium sulfate, filtered, and concentrated to givea solid residue, which was purified by flash chromatography(CH₂Cl₂:MeOH:NH₄OH 30:1:0.1) to give 13 as a white solid (195 mg, 0.663mmol, 66%): ¹H NMR (500 MHz, CDCl₃) δ 7.20 (d, 1H, J=8.1 Hz), 6.68 (d,1H, J=8.1 Hz), 5.71 (m, 1H), 5.30 (m, 1H), 5.02 (m, 1H), 4.24 (bs, 1H),3.38 (m, 1H), 3.12 (d, 1H, J=19.8 Hz), 2.68 (m, 3H), 2.44 (s, 3H), 2.33(m, 2H), 2.10 (m, 1H), 1.85 (m, 1H); MS (ESI) m/z 295 (M+H)⁺; Anal.Calcd. for C₁₈H₁₈N₂O₂.0.125H₂O: C 72.89, H 6.20, N 9.44. Found: C 72.74,H 6.14, N 9.28.

(B) Synthesis of 7,8-Dihydro-morphine-3-carbonitrile Derivative 14

A solution of compound 13 (81 mg, 0.28 mmol) and 10% Pd/C in 5 mL MeOHwas hydrogenated under the pressure of 40 psi. for 4 h at roomtemperature. The reaction mixture was filtered with celite, and thesolvent was removed to provide 14 as a foam (81 mg; 100%). ¹HNMR (CDCl₃)δ 7.20(d,1H, J=8.1 Hz), 6.69(d,1H, J=8.1 Hz), 4.7(s,1H), 3.12-3.09(m,1H), 3.0(d, 1H, J=19.5 Hz), 2.55(m, 1H), 2.44(m, 1H), 2.4(m,1H),2.35(s,3H), 2.25(m, 2H), 2.1(dd, 1H, J=4.2,12.0), 1.94-1.84(m, 2H),1.55(m, 1H), 1.4(m, 1H)). [α]_(D) ²⁵=−50.6° (c=0.64, CH₂Cl₂). MS m/z(ESI) 297(MH⁺).

(C) Synthesis of Hydrocodone-3-carbonitrile Derivative 15

Oxalyl chloride (41.9 μl, 0.47 mmol) was dissolved in 1 mL anhydrousCH₂Cl₂ under argon at −78° C. Dry DMSO (66.9 μl, 0.95 mmol) was thenadded. The reaction mixture stirred for 5 min and a solution of 14 (70mg, 0.24 mmol) in 1 mL dry CH₂Cl₂ was added by syringe. The mixturestirred for 20 min at −78° C. and 164 μl Et₃N was added to the reactionmixture and warmed to room temperature. The mixture was partitionedbetween water (10 mL) and CH₂Cl₂ (10 mL×3). The combined organic solventwas dried (MgSO₄), then concentrated in vacuo. The resulting compoundwas purified by flash column (silica gel,CH₂Cl₂:CH₃OH:NH₃/H₂O=20:1:0.01) to give 63.7 mg (92%) of 15 as a foam.¹HNMR (CDCl₃) δ 7.28(d,1H, J=8.1 Hz), 6.84(d,1H, J=8.1 Hz), 4.83(s,1H),3.24(t, 1H,J=2.4 Hz), 3.1(d, 1H, J=19.5 Hz), 2.66(m, 1H), 2.61(dt, 2H,J=2.4, 5.7 Hz), 2.46(m,1H), 2.44(s,3H), 2.33(m, 1H), 2.1(m, 1H),1.92-1.87(m, 1H), 1.75(m, 1H), 1.18(m, 1H)). [α]_(D) ²⁵=−64.4° (c=0.87,CH₂Cl₂). MS m/z (ESI) 295(MH⁺).

(D) Synthesis of 3-Carboxyamido-hydrocodone Derivative 16

A solution of 15 (72 mg, 0.25 mmol) and KOH in t-BuOH (10 mL) was heatedat reflux and stirred for 2 h. After cooling, the reaction mixture wasfiltered with celite, and the filtrate was concentrated. The residue waspurified by flash column (silica gel, CH₂Cl₂:CH₃OH:NH₃/H₂O=20:1:0.01) togive 64.9 mg (85%) of 16 as a foam. ¹HNMR (CDCl₃) δ 7.77(d,1H, J=8.1Hz),7.46(s, 1H), 6.82(d,1H, J=8.1 Hz), 5.89(s, 1H), 4.80(s,1H), 3.2(dd,1H, J=2.7,6.0 Hz), 3.1(d, 1H, J=19.5 Hz), 2.66(m, 1H), 2.62(m, 2H),2.46(m,1H), 2.44(s,3H), 2.33(d, 1H, J=5.4 Hz), 2.1(m, 1H), 1.92-1.87(m,1H), 1.75(m, 1H), 1.18(m, 1H)). [α]_(D) ²⁵=−96.6° (c=0.23, CH₂Cl₂). MSm/z (ESI) 313(MH⁺).

(E) Synthesis of 3-Carboxyamido-4-hydroxy-hydrocodone Derivative 17

A mixture of 16 (46 mg, 0.15 mmol), NH₄Cl (78.9 mg, 0.88 mmol), zincdust (57.3 mg, 0.88 mmol) and EtOH (95%, 15 mL) was heated at reflux for4 h. After cooling, the mixture was filtered, and the solids were washedwith NH₃/H₂O (2 mL). The combined filtrates and the washings wereconcentrated and extracted with CH₂Cl₂ (10 mL×3). The organic extractswere dried (MgSO₄) and concentrated. The residue was purified by columnchromatography (SiO₂, CH₂Cl₂:CH₃OH:NH₃/H₂O=10:1:0.01) to give 29 mg(63%) of 17 as a foam. ¹H NMR (CDCl3) δ 13.1(s, 1H), 7.12(dd,1H, J=1.2,8.1 Hz),7.46(s, 1H), 6.54(d,1H, J=8.1 Hz), 6.02(br, 2H), 4.35(d,1H,J=13.5 Hz), 2.99(m, 2H), 2.92(m, 1H), 2.7(dd, 1H, J=4.7, 13.9 Hz),2.46(m, 2H), 2.4(s,3H), 2.24(m,2H), 1.98(m, 1H), 1.87(m, 1H),1.6(m,1H)). [α]_(D) ²⁵=−25.9° (c=0.7, CHCl₃). MS m/z (ESI) 315(MH⁺).

Example 6 Synthesis of 3-Carboxamido-4-hydroxy-6α-hydroxy-nalbuphineDerivative 22a and 3-Carboxamido-4-hydroxy-6β-hydroxy-nalbuphineDerivative 22b

(A) Synthesis of Nalbuphine-3-triflate 18

To a dispersion of nalbuphine hydrochloride (714 mg, 1.812 mmol) inCH₂Cl₂ (30 mL) was added triethylamine (630 μL, 4.53 mmol) at 0° C.,followed by PhN(Tf)₂ (654 mg, 1.812 mmol) in one portion. The mixturewas allowed to warm to room temperature and stirred overnight. Thesolvent was removed under reduced pressure, and the residue waspartitioned between 6N NH₄OH solution (50 mL) and CH₂Cl₂ (3×50 mL). TheCH₂Cl₂ extracts were combined and the volume was reduced to 50 mL underreduced pressure. The organic phase was washed with saturated aqueousNa₂CO₃ solution (3×50 mL), then dried (Na₂SO₄) and concentrated to give18 (886 mg, 1.812 mmol, 100%). ¹H NMR (500 MHz, CDCl₃) δ 6.95 (d, 1H,J=8.5 Hz), 6.69 (d, 1H, J=8.5 Hz), 4.97 (broad, 1H), 4.75 (d, 1H, J=5.0Hz), 4.19 (m, 1H), 3.12 (d, 1H, J=19.0 Hz), 2.85 (d, 1H, J=6.0 Hz), 2.66(dd, 1H, J=19.0, 6.0 Hz), 2.52-2.44 (m, 4H), 2.25 (td, 1H, J=12.5, 5.0Hz), 2.17 (td, 1H, J=12.5, 3.0 Hz), 2.07 (m, 1H), 1.98-1.81 (m, 3H),1.73-1.44 (m, 5H), 1.26 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 149.5,134.4, 134.3, 130.2, 121.8, 119.6, 92.9, 69.8, 66.6, 62.7, 60.8, 47.0,43.4, 33.8, 32.8, 27.6, 27.1, 26.9, 23.8, 23.7, 18.9; MS (ESI) m/z 490(M+H)⁺.

(B) Synthesis of Nalbuphine-3-carbonitrile Derivative 19

To a three-neck flask equipped with a condenser was added compound 18(886 mg, 1.812 mmol), Zn(CN)₂ (638 mg, 5.436 mmol) and Pd(PPH₃)₄ (419mg, 0.362 mmol) under nitrogen atmosphere. The flask was sealed andremoved from the glove box. Anhydrous DMF (6 mL) was injected throughthe septum. The mixture was heated at 135° C. for 24 hours. DMF wasremoved under reduced pressure, and the residue was partitioned betweensaturated aqueous NaHCO₃ solution (100 mL) and ethyl acetate (3×100 mL).The organic extracts were combined, dried (Na₂SO₄) and concentrated togive crude product, which was purified by flash chromatography[(hexane/ethyl acetate/ammonium hydroxide (1:1:0.01)] to give compound19 as a while foam (549 mg, 1.50 mmol, 83%). ¹H NMR (500 MHz, CDCl₃) δ7.25 (d, 1H, J=8.0 Hz), 6.73 (d, 1H, J=8.0 Hz), 4.77 (d, 1H, J=5.0 Hz),4.23 (m, 1H), 3.15 (d, 1H, J=19.5 Hz), 2.86 (d, 1H, J=6.0 Hz), 2.69 (dd,1H, J=19.5, 6.0 Hz), 2.49 (m, 4H), 2.26 (td, 1H, J=13.0, 5.0 Hz), 2.15(td, 1H, J=11.5, 3.0 Hz), 2.06 (m, 3H), 1.90 (m, 1H), 1.84 (m, 2H), 1.65(m, 3H), 1.47 (m, 1H), 1.41 (m, 1H), 1.18 (m, 1H); ¹³C NMR (125 MHz,CDCl₃) δ 161.3, 139.8, 131.7, 131.3, 119.1, 115.8, 92.5, 90.4, 69.5,66.4, 62.3, 60.6, 46.1, 43.0, 33.5, 32.8, 27.7, 26.9, 26.7, 24.2, 23.4,18.7; MS (ESI) m/z 367 (M+H)⁺

(C) Synthesis of 6-Oxo-nalbuphine-3-carbonitrile Derivative 20

Oxalyl chloride (143 μL, 1.64 mmol) in CH₂Cl₂ (5 mL) was cooled to −78°C. under nitrogen atmosphere and anhydrous DMSO (232 μL, 3.27 mmol) wasadded via a syringe. After 2 minutes, compound 19 (335 mg, 0.915 mmol)in dry CH₂Cl₂ (5 mL) was added, and the stirring was continued for 15minutes. Dry triethylamine (570 μL, 4.097 mmol) was added, and thestirring was continued for 5 minutes. After warmed to room temperature,the reaction mixture was partitioned between saturated aqueous NaHCO₃solution (50 mL) and CH₂Cl₂ (3×50 mL). The combined organic layer waswashed with brine (100 mL), dried (Na₂SO₄) and concentrated to givecrude product, which was purified by flash chromatography [CH₂Cl₂/MeOH(25:1)] to give compound 20 (308 mg, 0.846 mmol, 92%). ¹H NMR (500 MHz,CDCl₃) δ 7.28 (d, 1H, J=8.0 Hz), 6.80 (d, 1H, J=8.0 Hz), 5.13 (broad,1H), 4.81 (s, 1H), 3.19 (d, 1H, J=19.5 Hz), 3.03 (td, 1H, J=14.5, 6.0Hz), 2.97 (d, 1H, J=6.0 Hz), 2.67 (dd, 1H, J=19.5, 6.0 Hz), 2.60-2.48(m, 4H), 2.44 (td, 1H, J=12.5, 5.5 Hz), 2.32 (m, 1H), 2.16-2.02 (m, 6H),1.70 (m, 2H), 1.53 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 206.2, 159.2,138.8, 132.0, 129.4, 119.5, 115.0, 92.7, 91.2, 69.8, 62.2, 60.3, 50.0,43.2, 35.9, 33.5, 31.2, 30.6, 26.9, 26.7, 24.0, 18.7; MS (ESI) m/z 365(M+H)⁺.

(D) Synthesis of 3-Carboxamido-4-hydroxy-6-oxo-nalbuphine Serivative 21

To a flask containing compound 20 (252 mg, 0.692 mmol) was added Zn dust(900 mg, 13.85 mmol), glacial acetic acid (5 mL) and concentrated HCl(0.69 mL, 8.3 mmol). After refluxing at 125° C. for 3 hours, thereaction mixture was cooled to 0° C. and concentrated NH₄OH solution wasadded to adjust pH to 10. The slurry mixture was extracted with CH₂Cl₂(3×100 mL). The organic extracts were combined, dried (Na₂SO₄) andconcentrated to yield 253 mg crude product. Flash chromatography gavecompound 21 (187 mg, 0.487 mmol, 71%). ¹H NMR (500 MHz, CDCl₃) δ 13.14(s, 1H), 7.13 (d, 1H, J=8.0 Hz), 6.56 (d, 1H, J=8.0 Hz), 6.30-5.40(broad, 2H), 4.65 (s, 1H), 4.04 (dd, 1H, J=11.0, 2.0 Hz), 3.02 (m, 1H),2.94 (d, 1H, J=13.0 Hz), 2.89 (m, 1H), 2.86 (m, 1H), 2.50 (m, 3H), 2.45(m, 1H), 2.16-1.71 (m, 9H), 1.68 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ212.5, 173.3, 162.0, 144.3, 127.2, 124.9, 117.5, 111.0, 68.9, 60.4,59.9, 45.6, 44.7, 43.9, 37.7, 33.8, 32.7, 32.1, 27.0, 26.8, 26.7, 18.7;IR (film) ν_(max) 3354, 2928, 1709, 1653, 1617, 1429 cm⁻¹; MS (ESI) m/z385 (M+H)⁺.

(E) Synthesis of 3-Carboxamido-4-hydroxy-6α-hydroxy-nalbuphineDerivative 22a and 3-Carboxamido-4-hydroxy-6β-hydroxy-nalbuphineDerivative 22b

Compound 21 (115 mg, 0.3 mmol) was dissolved in MeOH (2 mL) and cooledto 0° C. NaBH₄ (46 mg, 1.2 mmol) was added in one portion. The reactionwas stirred at 0° C. for two hours and quenched by the addition ofsaturated aqueous NH₄Cl solution. MeOH was removed under reducedpressure, and concentrated NH₄OH solution was added to adjust pH to 10.The aqueous phase was extracted with CHCl₃ (4×50 mL), and the organicextracts were combined, dried (NaSO₄) and concentrated to yield 97 mgcrude product. Flash chromatography [CHCl₃/MeOH/NH₄OH (10:1:0.1)] gaveisomers 22a (31.8 mg, 0.082 mmol, 17%) and 22b (40.7 mg, 0.105 mmol,35%). 22a: ¹H NMR (500 MHz, CDCl₃) δ 13.43 (s, 1H), 7.12 (d, 1H, J=8.0Hz), 6.62 (d, 1H, J=8.0 Hz), 6.30-5.30 (broad, 2H), 4.60 (s, 1H), 4.18(s, 1H), 3.47 (m, 1H), 3.01 (d, 1H, J=19.0 Hz), 2.95 (td, 1H, J=19.0,6.0 Hz), 2.66 (d, 1H, J=5.5 Hz), 2.47-2.37 (m, 4H), 2.10-1.85 (m, 10H),1.66-1.47 (m, 4H), 1.27 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 173.6,161.9, 144.3, 131.4, 123.9, 118.4, 110.5, 69.5, 67.8, 60.8, 60.4, 44.4,39.5, 35.2, 33.7, 33.1, 27.7, 27.00, 26.96, 26.93, 26.7, 18.7; IR (film)ν_(max) 3445 (broad), 2929, 1653, 1425 cm⁻¹; MS (ESI) m/z 387 (M+H)⁺.22b: ¹H NMR (500 MHz, CDCl₃) δ 13.10 (s, 1H), 7.15 (d, 1H, J=8.0 Hz),6.60 (d, 1H, J=8.0 Hz), 6.30-5.30 (broad, 2H), 4.46 (s, 1H), 3.53 (m,1H), 3.38 (m, 1H), 3.00 (d, 1H, J=19.5 Hz), 2.84 (td, 1H, J=19.5, 6.5Hz), 2.71 (d, 1H, J=6.0 Hz), 2.46-2.38 (m, 4H), 2.07-1.49 (m, 14H), 1.34(d, 1H, J=5.0 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 173.6, 161.0, 143.9,127.5, 124.5, 117.2, 110.3, 68.5, 66.7, 59.7, 59.6, 43.6, 41.4, 37.3,33.1, 31.6, 29.8, 29.7, 26.2, 25.9 (2C), 17.8; IR (film) ν_(max) 3410(broad), 2929, 1653, 1617, 1425 cm⁻¹; MS (ESI) m/z 387 (M+H)⁺.

Example 7 Synthesis of 3-Carboxamide-4-hydroxy-naltrexone Derivative 24

To a 50 mL of flask containing nitrile 23 (made using the procedure ofKubota et al., Tetrahedron Letters 39(19), 2907-2910 (1998)) (452 mg,1.29 mmol) was added 325 mesh zinc dust (1679 mg, 25.83 mmol), followedby the addition of 8 mL of glacial acetic acid and 1.29 mL of 12 M HCl.A condenser was installed and the reaction mixture was then refluxed at125° C. for 3 h. Some zinc balls formed at the bottom of the flask. Thereaction was cooled to 0° C. and concentrated NH₄OH was added dropwiseto adjust the pH to about 10. Formation of a white slurry was observed.The mixture was extracted with methylene chloride (100 mL×3). Theorganic phases were dried over sodium sulfate and concentrated to give alight yellow foam (484 mg), which was purified using flashchromatography (25:1:0.1 CH₂Cl₂:MeOH:NH₄OH) to give 3 as a white foam(264 mg, 0.713 mmol, 55%) and 24 as a white solid (100 mg, 0.281 mmol,22%): mp 268-270° C.; ¹H NMR (500 MHz, CDCl₃) δ 12.99 (s, 1H), 7.15 (d,1H, J=8.0 Hz), 6.60 (d, 1H, J=8.0 Hz), 6.60-5.40 (bs, 2H), 4.52 (bs,1H), 3.11 (m, 1H), 3.00-2.80 (m, 3H), 2.60 (m, 1H), 2.31 (m, 2H),2.10-1.70 (m, 4H), 1.60-1.35 (m, 5H), 1.18 (m, 1H), 0.83 (m, 1H), 0.50(m, 2H), 0.10 (m, 2H); MS (ESI) m/z 300 (M+H)⁺; Anal. Calcd. forC₂₁H₂₈N₂O₃.0.375H₂O: C 69.44, H 7.98, N 7.71. Found: C 69.46, H 8.11, N7.42. [α]_(D) ²⁵=−85.0° (c=0.40, CHCl₃).

Example 8 Synthesis of 3-Thiocarboxyamido-4-hydroxy-naltrexoneDerivative 26

(A) Synthesis of 3-Carbonitrile-4-hydroxy-naltrexone Derivative 25

To a 50 mL of flask containing nitrile 23 (101 mg, 0.28 mmol) was added325 mesh zinc dust (126 mg, 1.94 mmol) and ammonia hydrochloride (148mg, 2.77 mmol), followed by 4 mL of EtOH:H₂O (20:1). A condenser wasinstalled and the reaction mixture was then refluxed at 95° C. for 3 h.The reaction was cooled to room temperature and filtered through a cakeof celite. The celite was washed with MeOH. The filtrates wereconcentrated and then partitioned between CH₂Cl₂ (40 mL×3) and 40 mL ofNH₄OH in water (pH 8-9). The organic phases were combined, dried oversodium sulfate and concentrated to give a solid (106 mg), which waspurified using flash chromatography (25:1:0.1 CH₂Cl₂:MeOH:NH₄OH) to give25 as a white solid (63 mg, 0.17 mmol, 62%). ¹H NMR (500 MHz, CDCl₃) δ7.25 (d, 1H, J=9.3 Hz), 7.40 (d, 1H, J=7.8 Hz), 5.12 (bs, 1H), 3.81 (d,1H, J=12.6 Hz), 3.40-2.60 (m, 6H), 2.41 (s, 2H), 2.30-1.75 (m, 5H), 1.60(m, 1H), 0.88 (m, 1H), 0.56 (m, 2H), 0.14 (m, 2H); MS (ESI) m/z 300(M+H)⁺; [α]²⁵ _(D)=−64.3 (c=0.56°, EtOH).

(B) Synthesis of 3-Thiocarboxyamido-4-hydroxy-naltrexone Derivative 26

A mixture of nitrile 25 (49 mg, 0.139 mmol) and0,0-diethyl-dithiophosphoric acid (475 μL, 2.78 mmol) in water (2 mL)and ethanol (4 mL) was heated at 80° C. for 22 h. The reaction mixturewas cooled to room temperature and partitioned between saturated NaHCO₃(20 mL) and CH₂Cl₂ (20 mL×3). The organic phases were dried over sodiumsulfate and concentrated to give 26 as a yellow solid (56 mg), which waspurified using flash chromatography (40:1:0.1 EtOAc:MeOH:NH₄OH) to givea yellow foam (36 mg, 0.093 mmol, 67%). ¹H NMR (500 MHz, CDCl₃) δ 12.24(s, 1H), 7.20-7.06 (m, 3H), 6.59 (d, 1H, J=8.5 Hz), 4.72 (bs, 1H), 4.02(d, 1H, J=14.0 Hz), 3.14 (m, 1H), 2.94 (m, 2H), 2.94-2.70 (m, 2H), 2.65(m, 1H), 2.20-1.70 (m, 6H), 0.87 (m, 1H), 0.55 (m, 2H), 0.12 (m, 2H); MS(ESI) m/z 300 (M+H)⁺; Anal. Calcd. for C₂₁H₂₆N₂O₃S.0.25H₂O: C 64.51, H6.83, N 7.16. Found: C 64.50, H 6.61, N 6.94. [α]²⁵ _(D)=+85.0° (c=0.20,CHCl₃).

Each of the patents, patent applications, and references mentionedherein is hereby incorporated by reference in its entirety.

While typical embodiments have been set forth for the purpose ofillustration, the foregoing descriptions and examples should not bedeemed to be a limitation on the scope of the invention. Accordingly,various modifications, adaptations, and alternatives may occur to oneskilled in the art without departing from the spirit and scope of thepresent invention.

I claim:
 1. A compound of formula:


2. A pharmaceutically acceptable acid addition salt of a compound offormula:

wherein said salt is selected from acetic, benzenesulfonic (besylate),benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric acid or p-toluenesulfonic acidsalt.
 3. A method of treating pain comprising administering to a patientin need of such treatment a therapeutically effective amount of acompound of formula: